César Ríos-Navarro1, Luisa Hueso1, Ana Díaz2, Víctor Marcos-Garcés3, Clara Bonanad4, Amparo Ruiz-Sauri5, José M Vila6, María J Sanz7, Francisco J Chorro8, Laura Piqueras9, Vicente Bodi10. 1. Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain. 2. Unidad Central de Investigación Biomédica (UCIM), Universidad de Valencia, Valencia, Spain. 3. Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Valencia, Spain. 4. Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Valencia, Spain; Departamento de Medicina, Facultad de Medicina y Odontología, Universidad de Valencia, Valencia, Spain. 5. Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; Departamento de Patología, Facultad de Medicina y Odontología, Universidad de Valencia, Valencia, Spain. 6. Departamento de Fisiología, Facultad de Medicina y Odontología, Universidad de Valencia, Valencia, Spain. 7. Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain; Departamento de Farmacología, Facultad de Medicina y Odontología, Universidad de Valencia, Valencia, Spain. 8. Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Valencia, Spain; Departamento de Medicina, Facultad de Medicina y Odontología, Universidad de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. 9. Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain; Departamento de Farmacología, Facultad de Medicina y Odontología, Universidad de Valencia, Valencia, Spain. Electronic address: piqueras_lau@gva.es. 10. Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Valencia, Spain; Departamento de Medicina, Facultad de Medicina y Odontología, Universidad de Valencia, Valencia, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. Electronic address: vicente.bodi@uv.es.
Abstract
INTRODUCTION AND OBJECTIVES: Angiogenesis helps to reestablish microcirculation after myocardial infarction (MI). In this study, we aimed to further understand the role of the antiangiogenic isoform vascular endothelial growth factor (VEGF)-A165b after MI and to explore its potential as a coadjuvant therapy to coronary reperfusion. METHODS: Two mice MI models were formed: a) permanent coronary ligation (nonreperfused MI); b) transient 45-minute coronary occlusion followed by reperfusion (reperfused MI); in both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. We determined serum and myocardial VEGF-A165b levels. In both experimental MI models, we assessed the functional and structural role of VEGF-A165b blockade. In a cohort of 104 ST-segment elevation MI patients, circulating VEGF-A165b levels were correlated with cardiovascular magnetic resonance-derived left ventricular ejection fraction at 6 months and with the occurrence of adverse events (death, heart failure, and/or reinfarction). RESULTS: In both models, circulating and myocardial VEGF-A165b levels were increased 21 days after MI induction. Serum VEGF-A165b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A165b blockade increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in nonreperfused, MI experiments. In patients, higher VEGF-A165b levels correlated with depressed ejection fraction and worse outcomes. CONCLUSIONS: In experimental and clinical studies, higher serum VEGF-A165b levels are associated with worse systolic function. Their blockade enhances neoangiogenesis, reduces infarct size, and increases ejection fraction in reperfused, but not in nonreperfused, MI experiments. Therefore, VEGF-A165b neutralization represents a potential coadjuvant therapy to coronary reperfusion.
INTRODUCTION AND OBJECTIVES: Angiogenesis helps to reestablish microcirculation after myocardial infarction (MI). In this study, we aimed to further understand the role of the antiangiogenic isoform vascular endothelial growth factor (VEGF)-A165b after MI and to explore its potential as a coadjuvant therapy to coronary reperfusion. METHODS: Two mice MI models were formed: a) permanent coronary ligation (nonreperfused MI); b) transient 45-minute coronary occlusion followed by reperfusion (reperfused MI); in both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. We determined serum and myocardial VEGF-A165b levels. In both experimental MI models, we assessed the functional and structural role of VEGF-A165b blockade. In a cohort of 104 ST-segment elevation MI patients, circulating VEGF-A165b levels were correlated with cardiovascular magnetic resonance-derived left ventricular ejection fraction at 6 months and with the occurrence of adverse events (death, heart failure, and/or reinfarction). RESULTS: In both models, circulating and myocardial VEGF-A165b levels were increased 21 days after MI induction. Serum VEGF-A165b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A165b blockade increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in nonreperfused, MI experiments. In patients, higher VEGF-A165b levels correlated with depressed ejection fraction and worse outcomes. CONCLUSIONS: In experimental and clinical studies, higher serum VEGF-A165b levels are associated with worse systolic function. Their blockade enhances neoangiogenesis, reduces infarct size, and increases ejection fraction in reperfused, but not in nonreperfused, MI experiments. Therefore, VEGF-A165b neutralization represents a potential coadjuvant therapy to coronary reperfusion.